Processes for preparing 2-chloro-6-aminopurine-2'-deoxyribonucleoside (2-chloro-2'-deoxyadenosine, hereinafter"2-CdA") and other 2-chloro-6-aminopurines are known in the art. Such processes are described in, e.g., U.S. Pat. No. 4,760,137; Kazimierzuk et al., J. Am. Chem. Soc., 106:6379, 1984; Wright et al., J. Org. Chem., 52:4617, 1987 and Christensen et al., J. Med. Chem., 15:735, 1972. The preparation of 2-CdA described by these workers requires the glycosylation of a dihalogenated purine to give an intermediate dihalogenated nucleoside which is then transformed into the desired nucleoside. More specifically, these workers described the glycosylation of 2,6-dichloropurine with 1-chloro-2'-deoxy-3', 5'-di-O-p-toluyl-.beta.-D-erythropentofuranose to give a mixture of N-7 and N-9 isomers of 2,6-dichloro-(2'-deoxy-3', 5'-di-O-p-toluyl-.beta.-D-erythropentofuranosyl)-purine. This process suffers from several shortcomings, such as the formation of isomeric side products at the 1'-carbon and the utilization of costly starting materials, such as 2,6-dichloropurine.
U.S. Pat. No. 5,208,327 discloses a method for preparation of 2-CdA from guanosine in eight steps via a 2-chloroadenosine intermediate in 2.8% overall yield (from guanosine). This method is inefficient and requires several protection and deprotection steps in order to remove the 2' hydroxyl to yield a 2'-deoxy product. The synthesis of the 2-chloroadenosine intermediate also disclosed in the same patent uses protecting group chemistry and an alternate halogenation/amination strategy. This process is extremely expensive because of the multiple steps involved and the use of expensive 2-chloroguanosine starting material, and is not suitable for truly large scale production.
Processes for the preparation of compounds of the formula: ##STR2##
wherein R.sup.1 is acyl or tolyl and W.sup.1 and W.sup.2 are independently halogen or amino from the corresponding per-O-protected nucleosides are disclosed, e.g., in Robins & Uznanski, Can. J. Chem. 59, 2601, 1981; Montgomery & Hewson, J. Med. Chem. 12, 498, 1969; and Huang et. al. J. Med. Chem., 27, 800-802, 1984. The transformation of the starting nucleosides to 2-halopurines requires several steps, including diazotization of the 2-amino intermediates in non-polar organic solvents, followed by halogenation. Thus, this method is completely unfeasible when it is necessary to utilize starting materials that are not soluble or only sparingly soluble in non-polar organic solvents, in contrast to the methods of the present invention, detailed below.
Methods for the conversion of unprotected purine ribonucleosides having the formula: ##STR3##
wherein R.sup.1 is hydrogen, W.sup.3 is halogen or hydrogen, and W.sup.1 and W.sup.2 are independently amino or halogen, to 2-halogenated nucleosides are known in the art (Gerster et. al., J. Org. Chem., 33, 1070, 1968; Gerster et. al., J. Org. Chem., 31, 3258, 1966; Gerster et. al., J. Am. Chem. Soc, 87, 3752, 1965). However, these methods provide low yields of products, and require reactions to be performed with sodium nitrite at temperatures below 0.degree. C. in aqueous solution, thus making drying and separation of products difficult. The prior art also discloses that diazotization of 2-amino groups is only possible for ribonucleosides, because the reaction conditions cleave the glycosyl linkage of the corresponding deoxynucleosides (see Montgomery & Hewson, J. Med. Chem. 12, 498, 1969).
Thus, while the prior art discloses processes for the preparation of 2-CdA and other 2-halo-6-amino nucleosides and deoxynucleosides, these methods all have disadvantages, such as including a glycosylation reaction, or the need for a series of nucleoside hydroxyl protection/deprotection reactions, or the need to manipulate 2-halo-ribonucleosides or analogs at sub-zero temperatures using aqueous reaction conditions.
The present inventors have now surprisingly and unexpectedly discovered methods that make it possible to convert unprotected 2'- or 3'-deoxynucleosides, ribonucleosides or analogs to the corresponding 2-halo derivatives. Also discovered by the present inventors are methods for performing such transformations on unprotected nucleosides where the unprotected nucleosides are highly insoluble in non-polar organic solvents.